Adipose dysfunction links tightly to hepatic insulin resistance and gluconeogenesis. Ilexgenin A is reported with the ability to regulate lipid profile and protect the liver against high fat diet (HFD) -induced impairment. Here, we propose that ilexgenin A ameliorates hepatic insulin signaling and gluconeogenesis by regulating lipolysis in white adipose tissue (WAT). Pyruvate tolerance test and biochemical analysis coupled with the ex vivo siRNA knockdown and co-culture studies demonstrate that ilexgenin A suppresses inflammation-associated lipolysis in epididymal fat pad via 5′-AMP-activated protein kinase (AMPK) activation, thus inhibits diacylglycerol (DAG) accumulation and protein kinase C ε (PKCε) translocation in liver, leading to the improvement of insulin sensitivity and hepatic glucose production. These findings suggest that the relationship between adipose function and hepatic insulin action may be targeted by natural bioactive components for the potential treatment of hepatic insulin resistance related disorders.